This invention relates to cardiovascular agents and in particular to certain 1,4-dihydropyridines which combine both calcium antagonist and alpha.sub.1 -antagonist activity and which are useful for the treatment of hypertension, heart failure and angina.
The dihydropyridine calcium antagonists are well known as a class of therapeutic agents, the most widely used example being the compound nifedipine. Dihydropyridine derivatives substituted at the 2-position by side chains which include varous groups have been described in our published European patent applications nos. 60674 and 100189. Such compounds can reduce the movement of calcium into the cell and they are thus able to delay or prevent the cardiac contracture which is believed to be caused by an accumulation of intracellular calcium under ischaemic conditions. Excessive calcium influx during ischaemia can have a number of additional adverse effects which would further compromise the ischaemic myocardium. These include less efficient use of oxygen for ATP production, activation of mitochondrial fatty acid oxidation and possibly, promotion of cell necrosis. Thus calcium antagonists are useful in the treatment or prevention of a variety of cardiac conditions, such as angina pectoris, cardiac arrythmias, heart attacks and cardiac hypertrophy. Calcium antagonists also have vasodilator activity since they are thus also useful as antihypertensive agents and for the treatment of coronary vasospasm. Howver, with respect to the vasculature, calcium antagonists are primarily arteriolar dilators and the reflex sympathetic activation which occurs with nifedipine-like agents can be detrimental for both hpertensive and anginal patients. Alpha-.sub.1 -antagonits such as prazosin and doxazosin are also effective antihypertensive drugs but, since these agents act on both venous and arteriolar tone, heart rate changes are minor. In addition, alpha.sub.1 -antagonists have beneficial effects on high-density/low-density lipoprotein levels.
Combination of calcium- and alpha.sub.1 -antagonist properties in accordance with the present invention is advantageous since the clinical benefits associated with both pharmacological activities can be provided by a single agent. For example, these compounds possess anti-ischaemic, venodilator and arteriolardilator properties and are effective for the treatment of a wide range of cardiovascular disorders, particularly hypertension, heart failure and angina.
Quinazoline-dihydropyridines are disclosed as useful cardiovascular agents in U.S. application Ser. No. 562,482 filed Dec. 16, 1983 now U.S. Pat. No. 4,572,908.